Metabolic dysregulation occurs in many human diseases, including diabetes, cardiovascular diseases and cancer, and raises important questions as to the molecular mechanisms conflating these diseases. Recent reports suggest that metformin, a first-line medication for the treatment of type II diabetes particularly in obese patients, reduces the risk of cancer through its presumed effects on adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK plays a central role in maintaining energy homeostasis through its regulation of downstream cellular events including mTOR signaling, lipid catabolism, and glucose metabolism. The precise upstream events connecting metformin to AMPK may involve the serine/threonine kinase LKB1, which is also known as serine/threonine kinase-11 (STK11). In connection with our development of antineoplastic agents, we selected the process of AMPK activation as an initial guide for evaluating new, natural product-derived agents such as semisynthetic isoflavonoids. We utilize the terminology “isoflavones” to describe naturally occurring compounds and “isoflavonoids” to describe compounds with both the naturally occurring pharmacophore and man-made chemical modifications not seen in nature.